Poly(diallylamine)-based bile acid sequestrants

ABSTRACT

The present invention relates to a method for removing bile acids from a patient and certain polymers of use in the method. The method comprises the step of administering to the patient a therapeutically effective amount of a polymer composition which includes a a poly(diallylamine) polymer which is substituted with hydrophobic groups. The hydrophobic groups can be a substituted or unsubstituted, straight chain or branched C 3 –C 24 -alkyl group, an aralkyl group or an aryl group.

RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.09/286,341, filed Apr. 5, 1999, now U.S. Pat. No. 6,610,283 which is aContinuation of International Application No. PCT/US97/23899, whichdesignated the United States and was filed on Dec. 29, 1997, publishedin English and which is a Continuation-in-Part of U.S. Ser. No.08/777,408, filed Dec. 30, 1996, now U.S. Pat. No. 6,203,785. The entireteachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Salts of bile acids act as detergents to solubilize and, consequently,aid in the digestion of, dietary fats. Bile acids are derived fromcholesterol. Following digestion, bile acids can be passively absorbedin the jejunum or reabsorbed by active transport in the ileum. Bileacids which are not reabsorbed are deconjugated and dehydroxylated bybacterial action in the distal ileum and large intestine.

Reabsorption of bile acids from the intestine conserves lipoproteincholesterol in the bloodstream. Conversely, the blood cholesterol levelcan be reduced by hindering reabsorption of bile acids.

One method of reducing the amount of bile acids that are reabsorbed isoral administration of compounds that sequester the bile acids andcannot themselves be absorbed. The sequestered bile acids consequentlyare excreted. Serum cholesterol is then employed to produce more bileacids, thereby lowering the serum cholesterol level of the patient.

SUMMARY OF THE INVENTION

The present invention relates to a method for removing bile acids from apatient as well as certain polymers for use in the method. The methodcomprises the step of administering to the patient a therapeuticallyeffective amount of a polymer characterized by a diallylamine monomerwherein the amino nitrogen atom bears at least one hydrophobicsubstituent. The hydrophobic substituent can be a substituted orunsubstituted, straight chain or branched C₃–C₂₄-alkyl group, asubstituted or unsubstituted arylalkyl group or a substituted orunsubstituted aryl group. The polymer to be administered can behomopolymer or a copolymer.

In one embodiment, the polymer to be administered is a crosslinked orlinear poly(diallylamine) polymer wherein at least 10% of the aminonitrogen atoms are substituted by a C₃–C₂₄-alkyl group. In anotherembodiment, the polymer to be administered is characterized by adiallylamine monomer wherein the amino nitrogen atom bears an alkylgroup which is substituted with a quaternary ammonium group. Thenitrogen atom of the ammonium group can bear at least one terminalhydrophobic substituent.

The polymer to be administered can comprise secondary amino groups,tertiary amino groups or quaternary ammonium groups or a combinationthereof. Polymers which comprise secondary or tertiary amino groups canalso be administered in the form of salts of a pharmaceuticallyacceptable acid.

The polymer can be linear or crosslinked. In one embodiment, the polymeris crosslinked via the incorporation of a multifunctional comonomer. Inanother embodiment, the polymer is crosslinked via bridging groups whichlink amino nitrogen atoms on different polymer strands.

In another embodiment, the invention relates to poly(diallylamine)polymers which are useful as bile acid sequestrants. These polymers arecharacterized by an diallylamine monomer, or repeat unit, wherein theamino nitrogen bears an alkyl substituent which is substituted with anammonium group. The polymer can be a homopolymer or a copolymer.

The present invention offers the advantage that both substituted andunsubstituted diallylamines are readily polymerized and crosslinked, incomparison to other amine monomers. Such polymers also provide improvedefficacy over polymers utilized in prior art methods.

DETAILED DESCRIPTION OF THE INVENTION

The features and other details of the invention will now be moreparticularly described and pointed out in the claims. It will beunderstood that the particular embodiments of the invention are shown byway of illustration and not as limitations of the invention. Theprincipal features of the invention can be employed in variousembodiments without departing from the scope of the present invention.

The present invention is based on Applicants' discovery thatpoly(diallylamine) polymers comprising hydrophobic groups exhibitexcellent bile acid sequestration activity. The invention provides amethod for removing bile acids from a patient comprising administeringto the patient a therapeutically effective amount of a polymercharacterized by a diallylamine monomer, or repeat unit, wherein theamino nitrogen atom bears a hydrophobic substituent.

As used herein, the term “therapeutically effective amount” refers to anamount which is sufficient to remove a significant quantity of bileacids from the patient and, thus, to lower the serum cholesterol levelof the patient. The patient can be an animal, for example, a mammal, ora human.

A “hydrophobic substituent”, as the term is used herein, is a moietywhich, as a separate entity, is more soluble in octanol than water. Forexample, the octyl (C₈H₁₇) group is hydrophobic because its parentalkane, octane, has greater solubility in octanol than in water. Thehydrophobic substituent can be a saturated or unsaturated, substitutedor unsubstituted hydrocarbon group. Such groups include susbstituted andunsubstituted, normal, branched or cyclic alkyl groups having 3 or morecarbon atoms, substituted or unsubstituted arylalkyl or heteroarylalkylgroups and substituted or unsubstituted aryl or heteroaryl groups.

In one embodiment, the polymer to be administered is apoly(diallylamine) polymer characterized by a diallylamine monomerwherein the amino nitrogen atom bears at least one hydrophobicsubstituent selected from the group consisting of substituted orunsubstituted, normal, branched or cyclic C₃–C₂₄-alkyl groups, such as ahexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl ortetradecyl group; substituted or unsubstituted C₃–C₂₄-alkenyl groups,such as propenyl group; substituted or unsubstituted arylalkyl groups,such as a benzyl group; and substituted or unsubstituted aryl groups,such as a phenyl or naphthyl group. Suitable alkyl substituents includehalo (e.g. fluoro, chloro, bromo or iodo) groups, and alkoxy,cycloalkyl, substituted and unsubstituted, quaternary, amido, sulfone,sulfoxide, alkoxy and aryl groups. Suitable aryl and arylalkylsubstituents include fluoro, chloro, bromo, iodo, amino, ammonioalkyl,alkyl, alkoxy, hydroxy, alkoxy, sulfoxide and sulfone groups.

In one embodiment, at least 10% of the amino nitrogen atoms within thepolymer to be administered bear a hydrophobic substituent, such as aC₂–C₂₄-alkyl group. Preferably at least about 20% of the amino nitrogenatoms bear a hydrophobic substituent. In other embodiments, at leastabout 40% of the amino nitrogen atoms can bear a hydrophobicsubstituent.

In general, poly(diallylamine) polymers are characterized by monomers,or repeat units, comprising five-membered rings, monomers comprisingsix-membered rings, or a combination thereof. In one embodiment, thepolymer to be administered is characterized by an ammonium-bearingmonomer of Formula I or of Formula II

or a combination thereof, wherein R¹ is a hydrophobic substituent, asdescribed above, and R² is hydrogen, methyl, or a hydrophobicsubstituent. In a preferred embodiment, R¹ is selected from among theoctyl, decyl and dodecyl groups and R² is methyl.

X⁻ is an anion, such as the conjugate base of a pharmaceuticallyacceptable acid. Such anions include chloride, citrate, tartrate,lactate, phosphate, hydrophosphate, methanesulfonate, acetate, formate,maleate, fumarate, malate, succinate, malonate, sulfate, hydrosulfate,L-glutamate, L-aspartate, pyruvate, mucate, benzoate, glucuronate,oxalate, ascorbate and acetylglycinate. In a preferred embodiment, X⁻ ischloride.

In another embodiment, the polymer to be administered is characterizedby an amine-bearing monomeric unit of Formula III or Formula IV

or a combination thereof, wherein R is a hydrophobic substituent aspreviously described.

In a preferred embodiment, the polymer to be administered comprises oneor more monomers of Formulas I–IV wherein at least 10%, preferably atleast about 20%, of the amino nitrogen atoms bear a C₃–C₂₄-alkylsubstituent. Examples of particularly preferred C₃–C₂₄-alkyl groupsinclude hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyland tetradecyl groups.

The polymer to be administered can be a copolymer comprising one or morediallylamine monomers, such as one or more monomers of Formulas I, II,III, and IV, and at least one additional monomer. In one embodiment, theadditional monomer is sulfur dioxide. In polymers comprising sulfurdioxide, the polymer backbone includes —SO₂— units between pairs ofdiallylamine monomers.

In a further embodiment, the invention provides a method for removingbile acids from a patient comprising the step of administering to thepatient a therapeutically effective amount of a polymer characterized bya diallylamine repeat unit wherein the amino nitrogen atom bears anammonioalkyl substituent. The invention also includes theammonioalkyl-substituted polymers which are of use in this method.

The term “ammonioalkyl”, as used herein, refers to an alkyl group whichis substituted by a nitrogen atom bearing three additional substituents.Thus, the nitrogen atom is an ammonium nitrogen atom which bears analkylene substituent, which links this atom to the diallylamine nitrogenatom, and three additional substituents selected from among hydrogen,alkyl and arylalkyl. An ammonioalkyl group will further include anegatively charged counter ion, such as a conjugate base of apharmaceutically acceptable acid.

The diallylamine repeat unit can be, for example, of Formula I, FormulaII, Formula III, or Formula IV, wherein at least one of the nitrogensubstituents is an ammonioalkyl substituent. Suitable ammonioalkylsubstituents are of the general formula

wherein R⁴, R⁵ and R⁶ are each, independently, a hydrogen atom or aC₁–C₂₄ alkyl group; n is an integer from 2 to about 20, preferably from3 to about 6; and X⁻ is an anion, such as a conjugate base of apharmaceutically acceptable acid. Preferably, at least one of R⁴, R⁵ andR⁶ is a hydrophobic group such as a C₃–C₂₄-alkyl group. More preferably,at least one of R⁴, R⁵ and R⁶ is a C₆–C₂₄-alkyl group. Suitable examplesof ammonioalkyl groups include, but are not limited to,4-(dioctylmethylammonio)butyl; 3-(dodecyldimethylammonio)propyl;3-(octyldimethylammonio)propyl; 3-(decyldimethylammonio)propyl;5-(dodecyldimethylammonio)pentyl; 3-(cyclohexyldimethylammonio)propyl;3-(decyldimethylammonio)-2-hydroxypropyl; 3-(tridecylammonio)propyl;3-(docosyldimethylammonio)propyl; 4-(dodecyldimethylammonio)butyl;3-(octadecyldimethylammonio)propyl; 3-(hexyldimethylammonio)propyl;3-(methyldioctylammonio)propyl; 3-(didecylmethylammonio)propyl;3-(heptyldimethylammonio)propyl; 3-(dimethylnonylammonio)propyl;6-(dimethylundecylammonio)hexyl; 4-(heptyldimethylammonio)butyl;3-(dimethylundecylammonio)propyl; and3-(tetradecyldimethylammonio)propyl.

The polymer can be a homopolymer which comprises only a monomer selectedfrom among Formulas I–IV, above, wherein the nitrogen atom bears atleast one ammonioalkyl substituent. The polymer can also be a copolymerwhich comprises a monomer of this type and at least one additionalmonomer. For example, the polymer can comprise a second diallylaminemonomer wherein the nitrogen atom bears a substituent selected fromamong hydrogen, methyl, ethyl, hydrophobic groups and ammonioalkylgroups.

The polymer can also comprise an additional monomer which is not adiallylamine. Suitable examples of additional polymers includesubstituted and unsubstituted acrylate, acrylamide, methacrylate,methacrylamide, allylamine, allyl alcohol, vinyl amine and vinylalcohol. For example, the additional monomer can be a substitutedacrylate or acrylamide which bears a hydrophobic group, such as aC₃–C₂₄-alkylacrylate or an N—C₃–C₂₄-alkylacrylamide. The additionalmonomer can also be a hydrophilic monomer, such asN-(2-hydroxyethyl)acrylamide or (3-hydroxypropyl)acrylate. Also includedare the multifunctional crosslinking co-monomers which are discussed indetail below.

The copolymers can have a wide range of compositions. Typically, theammonioalkyl-substituted diallylamine monomer will constitute from about10% to about 90% of the monomeric units composing the polymer.

The polymers of use in the present method can be linear or crosslinked.The polymer can be crosslinked, for example, by the incorporation withinthe polymer of a multifunctional comonomer. Suitable multifunctionalco-monomers include diacrylates, triacrylates and tetraacrylates,dimethacrylates, diacrylamides, diallylacrylamide anddi(methacrylamides). Specific examples include ethylene glycoldiacrylate, propylene glycol diacrylate, butylene glycol diacrylate,ethylene glycol dimethacrylate, butylene glycol dimethacrylate,methylene bis(methacrylamide), ethylene bis(acrylamide), ethylenebis(methacrylamide), ethylidene bis(acrylamide), ethylidenebis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropanetriacrylate, bisphenol A dimethacrylate, and bisphenol A diacrylate.Other suitable multifunctional monomers include polyvinylarenes, such asdivinylbenzene. The amount of crosslinking agent is typically between1.0% and 25% by weight relative to the weight of the polymer, preferablyfrom about 2.5% to about 20% by weight and more preferably from about 2%to about 12% by weight.

The polymer can also be crosslinked by bridging units which link aminogroups on adjacent polymer strands. Suitable bridging units includestraight chain or branched, substituted or unsubstituted alkylenegroups, diacylalkylene groups, diacylarene groups and alkylenebis(carbamoyl) groups. Examples of suitable bridging units include—(CH₂)_(n)—, wherein n is an integer from about 2 to about 20;—CH₂—CH(OH)—CH₂—; —C(O)CH₂CH₂C(O)—;—CH₂—CH(OH)—O—(CH₂)_(n)—O—CH(OH)—CH₂—, wherein n is 2 to about 4;—C(O)—(C₆H₂(COOH)₂)—C(O)— and —C(O)NH(CH₂)_(p)NHC(O)—, wherein p is aninteger from about 2 to about 20.

Advantageously, crosslinking the polymers renders the polymersnon-adsorbable and stable in the patient. A “stable” polymercomposition, when administered in therapeutically effective amounts,does not dissolve or otherwise decompose to form potentially harmfulbyproducts, and remains substantially intact.

Polymers of use in the present method are, preferably, of a molecularweight which enables them to reach and remain in the gastrointestinaltract for a sufficient period of time to bind a significant amount ofone or more bile acids. The polymers should, thus, be of sufficientlyhigh molecular weight to resist, partially or completely, absorptionfrom the gastrointestinal tract into other regions of the body. Theresulting polymer/bile salt complex should then be excreted from thebody. Suitable linar (non-crosslinked) polymers have molecular weightswhich range from about 2,000 Daltons to about 500,000 Daltons,preferably from about 5,000 Daltons to about 150,000 Daltons.Crosslinked polymers, however, are not generally chaacterized bymolecular weight. The crosslinked polymers discussed herein should besufficiently crosslinked to resist adsorption from the gastrointestinaltract.

The polymer network can be administered orally to a patient in a dosageof about 1 mg/kg/day to about 10 g/kg/day; the particular dosage willdepend on the individual patient (e.g., the patient's weight and theextent of bile salt removal required). The polymer can be administeredeither in hydrated or dehydrated form, and can be flavored or added to afood or drink, if desired, to enhance patient acceptance. Additionalingredients such as other bile acid sequestrants, drugs for treatinghypercholesterolemia, atherosclerosis or other related indications, orinert ingredients, such as artificial coloring agents, may be added aswell.

Examples of suitable forms for administration include pills, tablets,capsules, and powders (i.e. for sprinkling on food). The pill, tablet,capsule or powder can be coated with a substance capable of protectingthe composition from the gastric acid in the patient's stomach for aperiod of time sufficient for the composition to pass undisintegratedinto the patient's small intestine. The polymer can be administeredalone or in combination with a pharmaceutically acceptable carrier,diluent or excipient substance, such as a solid, liquid or semi-solidmaterial. Examples of suitable carriers, diluents and excipients includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,alginates, tragacanth, gelatin, calcium silicate, cellulose and othersknown in the art.

Polymers of use in the present method can be prepared using techniquesknown in the art of polymer synthesis (see for example, Shalaby et al.,ed., Water-Soluble Polymers, American Chemical Society, Washington D.C.(1991)). For example, the appropriate monomer can be polymerized bymethods known in the art, for example, via a free radical additionprocess. In this case the polymerization mixture includes a free-radicalinitiator, such as a free radical initiator selected from among thosewhich are well known in the art of polymer chemistry. Suitablefree-radical initiators include azobis(isobutyronitrile),azobis(4-cyanovaleric acid), azobis(amidinopropane) dihydrochloride,potassium persulfate, ammonium persulfate and potassium hydrogenpersulfate. The free radical initiator is preferably present in thereaction mixture in an amount ranging from about 0.1 mole percent toabout 5 mole percent relative to the monomer.

The polymer can be crosslinked, for example, by including amultifunctional co-monomer as the crosslinking agent in the reactionmixture. A multifunctional co-monomer can be incorporated into two ormore growing polymer chains, thereby crosslinking the chains. Suitablemultifunctional co-monomers include those discussed above. The amount ofcrosslinking agent added to the reaction mixture is, generally, between1.0% and 25% by weight relative to the combined weight of the polymerand the crosslinking agent, and preferably from about 2.5% to about 20%by weight.

The multifunctional co-monomer can also take the form of amultifunctional diallylamine, such as a bis(diallylamino)alkane or abis(diallylalkylammonio) alkane. Suitable monomers of this type include1,10-bis(diallylmethylammonio)decane dibromide and1,6-bis(diallylmethylammonio)hexane, each of which can be formed by thereaction of diallylmethylamine with the appropriate dibromoalkane.

The polymers to be administered can also be crosslinked subsequent topolymerization by reacting the polymer with one or more crosslinkingagents having two or more functional groups, such as electrophilicgroups, which react with amine groups to form a covalent bond.Crosslinking in this case can occur, for example, via nucleophilicattack of the polymer amino groups on the electrophilic groups. Thisresults in the formation of a bridging unit which links two or moreamino nitrogen atoms from different polymer strands. Suitablecrosslinking agents of this type include compounds having two or moregroups selected from among acyl chloride, epoxide, and alkyl-X, whereinX is a suitable leaving group, such as a halo, tosyl or mesyl group.Examples of such compounds include epichlorohydrin, succinyl dichloride,butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromelliticdianhydride and dihaloalkanes. The crosslinking agent can also be anα,ω-alkylene diisocyanate, for example OCN(CH₂)_(p)NCO, wherein p is aninteger from about 2 to about 20. The polymer can be reacted with anamount of crosslinking agent equal from about 0.5 and 20 mole percentrelative to the amino groups within the polymer, depending upon theextent of crosslinking desired.

A polymer comprising alkylated amino groups can be formed by reacting apreformed polymer with a suitable alkylating agent, or by polymerizingan alkylated monomer. Suitable alkylated monomers can be prepared byreacting diallylamine or a diallylamine derivative, such asdiallylmethylamine, with an alkylating agent. As used herein, the term“alkylating agent” refers to a compound which reacts with an amino groupto form a nitrogen-carbon bond, thereby adding an alkyl or alkylderivative substituent to the nitrogen atom. Suitable alkylating agentsare compounds comprising an alkyl group or alkyl derivative which isbonded to a leaving group, such as a halo, tosylate, mesylate or epoxygroup. Examples of preferred alkylating agents include C₁–C₂₄-alkylhalides, for example, n-butyl halides, n-hexyl halides, n-decyl halides,and n-octadecyl halides; C₂–C₂₄-dihaloalkanes, for example,1,10-dihalodecanes; C₁–C₂₄-hydroxyalkyl halides, for example,11-halo-1-undecanols; C₁–C₂₄-arylalkyl halides, for example, benzylhalide; C₂–C₂₄-alkylepoxy ammonium salts, for example,glycidylpropyl-trimethylammonium salts; and C₂–C₂₄-epoxyalkylamides, forexample, N-(2,3-epoxypropyl)butyramide or N-(2,3-epoxypropyl)hexanamide.Preferred alkylating agents include halodecane, and halododecane, wherein each case “halo” represents a chloro, bromo or iodo substituent.

Diallylamine polymers having amino groups which bear quaternaryammonium-substituted alkyl groups can be prepared using alkylatingagents such as (X-alkyl)ammonium salts, wherein X represents a suitableleaving group, as described above. These compounds can be prepared bythe reaction of an appropriate dihaloalkane, such as abromochloroalkane, with a tertiary amine. Suitable alkylating agents ofthis type include the following:

-   (4-bromobutyl)dioctylmethylammonium bromide;-   (3-bromopropyl)dodecyldimethylammonium bromide;-   (3-chloropropyl)dodecyldimethylammonium bromide);-   (3-bromopropyl)octyldimethylammonium bromide;-   (3-chloropropyl)octyldimethylammonium bromide;-   (3-iodobutyl)dioctylmethylammonium bromide;-   (2,3-epoxypropyl)decyldimethylammonium bromide;-   (3-chloropropyl)decyldimethylammonium bromide;-   (5-tosylpentyl)dodecyldimethylammonium bromide;-   (6-bromohexyl)octyldimethylammonium bromide;-   (12-bromododecyl)decyldimethylammonium bromide;-   (3-bromopropyl)tridecylammonium bromide;-   (3-bromopropyl)docosyldimethylammonium bromide;-   (6-bromohexyl)docosyldimethylammonium bromide;-   (4-chlorobutyl)dodecyldimethylammonium bromide;-   (3-chloropropyl)octadecyldimethylammonium bromide;-   (3-chloropropyl)hexyldimethylammonium bromide;-   (3-chloropropyl)methyldioctylammonium bromide;-   (3-chloropropyl)methyldidecylammonium bromide;-   (3-chloropropyl)cyclohexyldimethylammonium bromide;-   (3-bromopropyl)heptyldimethylammonium bromide;-   (3-bromopropyl)dimethylnonylammonium bromide;-   (6-bromohexyl)dimethylundecylammonium bromide;-   (4-chlorobutyl)heptyldimethylammonium bromide;-   (3-chloropropyl)dimethylundecylammonium bromide; and-   (3-chloropropyl)tetradecyldimethylammonium bromide.

Each of the alkylating agents described above can also exist and be usedas a salt in combination with an anion other than bromide. For example,these and similar alkylating agents can be prepared and used as saltswith a wide range of anions, including chloride, iodide, acetate,p-toluenesulfonate and methanesulfonate.

When the hydrophobic groups are added to the polymer by way of analkylating agent as described above, the extent of alkylation can bedetermined by methods which are well known in the chemical arts. Theincrease in polymer mass due to alkylation provides one measure of theextent of alkylation. For example, in a reaction betweenpoly(diallylmethylamine) and 1-bromodecane, a product/starting materialmass ratio of about 3.0, 2.0 and 1.5 represent approximately 100%, 50%and 25% alkylation, respectively. The degree of alkylation can also bedetermined by elemental analysis of the product polymer. In this case,the carbon/nitrogen (C/N) mass ratio is a direct measure of the degreeof alkylation. For example, the reaction of poly(diallylmethylamine)with 1-bromodecane yields a product with a higher C/N mass ratio thanthat of the starting polymer. Product C/N mass ratios of about 6, 8.2,10.6 and 14.6 represent, approximately, 0%, 25%, 50% and 100%alkylation, respectively.

The invention will now be further and specifically described by thefollowing examples.

EXAMPLES Example 1 Synthesis of Diallylmethyldodecylammonium bromide

To a 2 L Morton flask was added diallylmethylamine (100 g),1-bromododecane (249 g), and tetrahydrofuran (750 mL). The mixture washeated to 65° C. for 44 h, and then allowed to cool to room temperature.The solvent was removed by rotary vacuum evaporation to leave twolayers. Diethylether (500 mL) was added and the mixture was stirred for1 hr. The mixture was allowed to settle and the top layer was decantedand discarded. Additional diethylether (500 mL) was added. The mixturewas stirred for 24 h, and the top layer was again decanted anddiscarded. The remaining oil was dried in a vacuum oven at 65° C. for 4days to yield 67 g of product.

Example 2 Synthesis of 1,10-Bis(diallylmethylammonio)decane dibromide

To a 1 L Morton flask was added diallylmethylamine (86.1 g),1,10-dibromodecane (112 g), and methanol (100 mL). The mixture washeated to 65° C. for 24 h, and then allowed to cool to room temperature.The solvent was removed by rotary vacuum evaporation. Diethylether (400mL) was added and the mixture was stirred for 1 hr. The mixture wasallowed to settle and the top layer was decanted and discarded. Theremaining oil was dried by rotary vacuum evaporation to yield 215 g ofproduct.

Example 3 Synthesis of 1,6-Bis(diallylmethylammonio)hexane dibromide

To a 1 L Morton flask was added diallylmethylamine (74.6 g),1,6-dibromohexane (77 g), and methanol (100 mL). The mixture was heatedto 65° C. for 17 h, and then allowed to cool to room temperature.Diethylether (300 mL) was added and the mixture was stirred for 1 hr.The solid was collected by filtration and resuspended in diethylether(200 mL). The mixture was stirred for 1 hr, and the solid againcollected by filtration. The solid was then dried in a vacuum oven at50° C. for 3 days to yield 136 g of product.

Example 4 Synthesis of Poly[1,10-bis(diallylmethylammonio)-decanedibromide]

To a 250-mL, round bottom flask was added 1,10-bis(diallylmethylammonio)decane dibromide (20 g) and water (40 g). Azobisisobutyramidinedihydrochloride (0.5 mL of a 50% aqueous solution) was added andnitrogen was bubbled through the mixture for 1 hr. The mixture was thenheated to 60° C. with stirring for 4 hr, at which time additionalazobisisobutyramidine dihydrochloride (0.5 mL of a 50% aqueous solution)was added.

After 18 hr the solution was allowed to cool to room temperature. Theresulting gel was removed and ground in a blender with water (500 mL).The solid was collected by centrifugation and resuspended in methanol(500 mL). After stirring for 1 hr, the solid was collected by filtrationand resuspended in aqueous NaCl (500 mL of 1.5 M solution). After againstirring for 1 hr, the solid was collected by filtration. The aqueousNaCl rinse was repeated twice more, and the solid was rinsed with wateruntil the conductivity of the rinse reached 0.3 mS/cm. The solid wasdried in a forced air at 60° C. to yield 10.0 g of product.

Example 5 Synthesis of Copoly[1,10-bis(diallylmethylammonio)decanedibromide/diallylmethyldodecylammonium bromide]

To a 500-mL round bottom flask was added 1,10-bis(diallylmethylammonio)decane dibromide (21.1 g), diallylmethyldodecylammonium bromide (21.1g), and water (52 g). Azobisisobutyramidine dihydrochloride (1 mL of a50% aqueous solution) was added and nitrogen was bubbled through themixture for 1 hr. The mixture was then heated to 60° C. with stirringfor 18 hr. The resulting gel was allowed to cool to room temperature.The gel was removed and ground in a blender with water (250 mL). Thesolid was collected by filtration and resuspended in methanol (250 mL).The solid was collected by filtration and resuspended in methanol (250mL). After stirring for 1 hr, the solid was collected by filtration andresuspended in aqueous NaCl (250 mL of 1.5 M solution). After againstirring for 1 hr, the solid was collected by filtration. The aqueousNaCl rinse was repeated twice more, and the solid was rinsed with wateruntil the conductivity of the rinse reached 0.08 mS/cm. The solid wasdried in a forced-air oven at 60° C. to yield 17.6 g of product.

Example 6 Synthesis of Epichlorohydrin CrosslinkedPoly(diallylmethylamine)

A crosslinked gel of N-methyl-N; N-diallylamine polymer was prepared byreacting the corresponding linear soluble polymer with epichlorohydrin.The starting material, poly(diallylmethylamine) was obtained in the formof its hydrochloride salt from Nitto Boseki Co. The polymer was obtainedas a 60% aqueous solution (PAS-M-1, Lot # 51017). The chemical processto obtain insoluble gels of this polymer involved partial neutralizationof the amine hydrochloride polymer with a base followed by treatmentwith a predetermined amount of epichlorohydrin at room temperature.Experimental details to obtain a typical crosslinked gel ofpoly(diallylmethylamine hydrochloride) are given below.

83 g of the polymer solution was diluted with 170 mL deionized water.While stirring, 6.8 g NaOH was added to the polymer solution. Thereaction mixture was allowed to stir until all NaOH had dissolved. Whenthe temperature of the solution had dropped to below 30° C.,epichlorohydrin (1.2 mL) was added and stirring continued. The reactionmedium slowly became viscous and after about 80 minutes, had gelled andthe stirring was stopped. The polymer gel was left at room temperaturefor an additional 60 hr. The polymer slab was broken into smaller piecesand dispersed in 400 mL deionized water. The resulting suspension wasstirred for 2 hr and then filtered. The swollen polymer particles wereresuspended in 600 mL deionized water, stirred for 45 minutes andcollected by filtration. The process was repeated with 800 mL water and1 hr stirring. After filtration, the filtrate showed a conductivity of 4mS/cm. The filtered polymer (swollen gel) was dried in a forced air ovenat 60° C. to yield 42 g of product.

Example 7 Alkylation of Crosslinked Poly(diallylmethylamine) with1-bromodecane

25 g of the ground polymer (Example 6) taken in a 1 liter 3-necked roundbottom flask was suspended in 250 mL deionized water. The polymerswelled significantly and was stirred with a mechanical stirrer. To thisswollen gel was added 100 g 1-bromodecane dissolved in 250 mL ethanoland the reaction mixture was stirred for 10 minutes. Subsequently, 5 gof 50% aqueous sodium hydroxide was added and the reaction mixture wasstirred at room temperature for 40 minutes followed by heating to 75° C.for 1 hr. 2 g NaOH solution was then added followed by additional 2 g ofNaOH solution after another 1.5 hr (the base addition was such as tomaintain the pH between 10 and 12). The reaction mixture was stirred at75° C. for an additional 18 hours, after which time heating wasdiscontinued. After cooling to 30° C., 5 mL concentrated HCl was addedand stirring was continued for 30 minutes. The pH of the medium droppedto 1.8. The polymer was filtered and washed with 500 mL deionized waterfollowed by 500 mL methanol. Polymer particles were suspended in 600 mLmethanol and stirred for 40 minutes. After removing the solvent byfiltration, the polymer was suspended in 500 mL of 2 M NaCl solution andstirred for 40 minutes. The polymer was filtered and this process ofNaCl treatment was repeated two more times. The filtered polymer cakewas washed with 500 mL deionized water and suspended in 500 mL deionizedwater. After stirring for 30 minutes the polymer was filtered andresuspended in 700 mL deionized water and stirred for 30 minutes.Concentrated HCl (2 mL) was added to the suspension and the mixture wasstirred for 15 minutes. The pH of the suspension was found to be 2.25.After stirring for an additional 20 minutes, the polymer was filteredand dried at 60° C. in a forced air oven, yielding 54.6 g of thealkylated polymer as a light yellow solid. The polymer was ground andpassed through a 140 mesh sieve.

Example 8 Alkylation of Crosslinked poly(diallylmethylamine) with1-bromododecane

10 g of the ground polymer (Example 6) was suspended in 100 mL deionizedwater in a 500 mL 3-necked round-bottomed flask. The polymer swelledsignificantly and was stirred with a mechanical stirrer. To this swollengel, 28 g 1-bromodecane dissolved in 100 mL ethanol was added and thereaction mixture was stirred for 10 minutes. 2 g of 50% aqueous sodiumhydroxide was then added and the reaction mixture was stirred at roomtemperature for 40 minutes, followed by heating to 75° C. for 1 hr. 1 gNaOH solution was then added followed by an additional 1 g of NaOHsolution after another 1.5 hr (the base addition was such as to maintainthe pH between 10 and 12). The reaction mixture was stirred at 75° C.for an additional 18 h after which time the heating discontinued. Aftercooling to 30° C., concentrated HCl (2 mL) was added and the mixture wasstirred for 30 minutes. The polymer was filtered and washed with 500 mLdeionized water followed by 500 mL methanol. Polymer particles weresuspended in 300 mL methanol and stirred for 40 minutes. After removingthe solvent by filtration, the polymer was suspended in 500 mL 2M NaClsolution and stirred for 40 minutes. It was filtered and this process ofNaCl treatment was repeated two more times. The filtered polymer cakewas washed with 500 mL deionized water and suspended in 500 mL deionizedwater. After stirring for 30 minutes the polymer was filtered andresuspended in 500 mL deionized water and stirred for 30 minutes.Concentrated HCl (2 mL) was added to the suspension and the mixture wasstirred for 15 minutes. The pH of the suspension was found to be 2.2.After stirring for an additional 20 minutes, the polymer was filteredand dried at 60° C. in a forced air oven, yielding 18 g of the alkylatedpolymer as a pale white solid. The polymer was ground and passed througha 140 mesh sieve.

Example 9 Preparation of (3-chloropropyl)-dodecyldimethylammoniumbromide

A two-liter, 3-necked, round-bottomed flask equipped with an aircondenser and a magnetic stirring plate was charged withN,N-dimethyldodecylamine (297.24 grams, 1.40 moles),1-bromo-3-chloropropane (220.44 grams, 1.40 moles) and methanol (250mL). Reaction was maintained at 65° C. for 24 hours. Methanol wasremoved by rotary evaporation under reduced pressure to yield a brownsludge. To the sludge was added methyl-tert-butylether (2 liters)causing a white solid to form. The mixture was stirred for two hours anda semi-crystalline, white particulate was collected by vacuumfiltration. The particulate was dried in a vacuum oven at 35° C. for 24hours. Yield 228.2 grams (0.61 moles, 44%).

(4-Chlorobutyl)dodecyldimethylammonium bromide and (6-chlorohexyl)dodecyldimethylammonium bromide can be prepared by a similar processusing the appropriate bromochloroalkane and dodecyldimethylamine.

Example 10 Alkylation of Crosslinked Poly(diallylmethylamine) with(3-chloropropyl)dimethyldodecylammonium bromide

A mixture of 11 g crosslinked polymer gel (Example 6) and 74 g(3-chloropropyl)-dimethyldodecylammonium bromide was dispersed in 250 mLdeionized water and heated to 75° C. with stirring. After stirring at75° C. for 15 minutes, 2 g of a 50% aqueous NaOH solution was added tothe reaction mixture. After 2 hr, 1 g of NaOH solution was addedfollowed by an additional 1 g after another 1 hr and the mixture wasstirred at 75° C. for 23 hr. The reaction mixture was then allowed tocool. After cooling to 30° C., 3 mL concentrated HCl was added and themixture was stirred for 30 minutes. The polymer was filtered and washedwith 200 mL methanol. The filtered polymer particles were dispersed in400 mL methanol and stirred for 45 minutes and filtered. This processwas repeated one more time, then the filtered polymer was suspended in500 mL 2M NaCl solution, stirred for 45 minutes and filtered. Thisprocess of NaCl treatment was repeated twice and the filtered polymerwas suspended in 500 mL deionized water. The mixture was stirred for 45minutes, filtered, resuspended in 400 mL deionized water and stirred foran additional 40 minutes. To this suspension, 1 mL concentrated HCl wasadded and the mixture was stirred for 20 minutes. The polymer wasfiltered and dried in a forced air oven at 60° C., yielding 29 g ofalkylated polymer as a light yellow solid which was ground and passedthrough a 140 mesh sieve.

Example 11 Alkylation of Crosslinked Poly(diallylmethylamine) with(4-chlorobutyl)dimethyldodecylammonium bromide

A mixture of 10 g 3% crosslinked polymer gel (Example 6) and 76 g(4-chlorobutyl)dimethyldodecyl-ammonium bromide was dispersed in 250 mLdeionized water and heated to 70° C. with stirring for 15 minutes. 2 g50% aqueous solution of NaOH was then added to the reaction mixture.After 2 hr, 1 g NaOH solution was added followed by additional 1 g afteranother 2 hr. The reaction mixture was then stirred at 70° C. for 20hours. 1 g NaOH was then added and the reaction mixture was kept at 70°C. After 20 hr heating, 1 g NaOH solution was added and the reactionmixture was kept at 70° C. with stirring for 2 hr. After cooling to 30°C., 2 mL of concentrated HCl was added and the mixture was stirred for20 minutes. The polymer was filtered and washed successively with 200 mLdeionized water and 200 mL methanol. The filtered polymer particles werethen dispersed in 500 mL methanol, stirred for 30 minutes, and filtered.This process was repeated an additional time and the filtered polymerwas suspended in 400 mL 2M NaCl solution, stirred for 45 minutes andfiltered. After repeating NaCl treatment twice, the filtered polymer wassuspended in 400 mL deionized water. The mixture was stirred for 30minutes, filtered, resuspended in 400 mL deionized water and stirred foran additional 40 minutes. To this polymer suspension, 1 mL concentrated.HCl was added and the mixture was stirred for 20 minutes. The polymerwas then filtered and dried in a forced air oven at 60° C., yielding 27g alkylated polymer as a light yellow solid which was ground and passedthrough a 140 mesh sieve.

Example 12 Alkylation of Crosslinked Poly(diallylmethylamine) with(6-chlorohexyl)-dimethyloctylammonium bromide

A mixture of 10 g 3% crosslinked polymer gel (Example 6) and 71 g(6-chlorohexyl)dimethyldodecyl-ammonium bromide was dispersed in 200 mLdeionized water and heated to 75° C. with stirring for 15 minutes. 2 g50% aqueous solution of NaOH was then added to the reaction mixture.After 3 hr, 1 g NaOH solution was added. After 2.5 hr an additional 1 gof NaOH solution was added and the reaction mixture was stirred at 75°C. for 22 hr. 0.5 g NaOH was then added and heating was continued for anadditional 2 hr. After cooling to 30° C., 2 mL concentrated HCl wasadded and the mixture was stirred for 15 minutes. The polymer was thenfiltered and washed successively with 200 mL deionized water and 200 mLmethanol. The filtered polymer particles were then dispersed in 500 mLmethanol, stirred for 30 minutes and filtered. This process was repeatedtwo times, then the filtered polymer was suspended in 400 mL 2M NaClsolution, stirred for 45 minutes and filtered. After repeating the NaCltreatment twice, the filtered polymer was suspended in 400 mL deionizedwater. The mixture was stirred for 30 minutes, filtered, and resuspendedin 400 mL deionized water and stirred for an additional 40 minutes. Tothis polymer suspension was added 1 mL concentrated HCl and the mixturewas stirred for 20 minutes. The polymer was filtered and dried in aforced air oven at 60° C., yielding 25 g alkylated polymer as a whitesolid, which was ground and passed through a 140 mesh sieve.

Example 13 Alkylation of Crosslinked Poly(diallylmethylamine) with1-bromodecane

This example illustrates alkylation of the 4.5% crosslinkedpoly(diallylmethylamine) with different amounts of 1-bromodecane toobtain quaternized polyamines bearing varying amounts of hydrophobicgroups. For this purpose, the polymer was treated with varying molefractions of 1-bromodecane (1.0, 0.75, 0.50, 0.25 and 0.10). Table 1summarizes amounts of 1-bromoalkane used to obtain polymers of varyingdegree of alkylation and the yield of alkylated polymer per gram of the4.5% crosslinked poly (diallylmethylamine) (Example 2). This g/g yieldis a measure of the degree of alkylation of the polymer.

10 g of the 4.5% crosslinked poly(diallylmethyl-amine) was suspended in150 mL deionized water. While stirring, 2 g 50% aqueous NaOH solutionwas added to the polymer and the suspension was stirred for 15 minutes.At this time an ethanol solution of 1-bromodecane (2.5 mL ethanol/g1-bromodecane) was added and the reaction mixture was heated to 75° C.with stirring. After 2 hr, 1 g NaOH was added, followed by an additional1 g of NaOH after another 2 hr. The reaction mixture was stirred at 75°C. for 18 hours and was then allowed to cool. After cooling to 30° C., 2mL concentrated HCl was added and the mixture was stirred for 15minutes. The polymer was filtered and washed with 200 mL deionized waterand 200 mL methanol for 30 minutes and filtered. This process wasrepeated twice and the filtered polymer was suspended in 400 mL of 2MNaCl solution, stirred for 45 minutes and filtered. After repeating theNaCl treatment twice, the filtered polymer was suspended in 400 mLdeionized water. The mixture was stirred for an additional 30 minutes,filtered, resuspended in 400 mL deionized water and stirred for anadditional 40 minutes. To this polymer suspension was added 1 mLconcentrated HCl and the mixture was stirred for 20 minutes. The polymerwas filtered, dried in a forced air oven at 60° C., ground and passedthrough a 140 mesh sieve. Yield of the polymers for different amounts ofthe 1-bromodecane used are summarized in Table 1. The calculation of %alkylation assumed protonation of 50% of the amino nitrogen atoms.

TABLE 1 Results of the alkylation of 4.5% crosslinkedpoly(diallylmethylamine) with varying amounts of 1-bromodecane(C₁₀H₂₁Br) (“ratio” = ratio of 1-bromodecane to polymer amino groups(mole/mole)). product/ Polymer C₁₀H₂₁Br product starting Used used yieldpolymer (g) (g) Ratio (g) (g/g) % alkylation 10.0 17.0 1.0 17 1.7 3510.0 12.5 0.75 16.8 1.68 34 10.0 8.0 0.50 14.3 1.43 22 10.0 4.25 0.2511.8 1.18 9 10.0 1.70 0.10 10.6 1.06 3

Example 14 Alkylation of Crosslinked Poly(diallylmethylamine) with1-bromotetradecane

10 g of 4.5% crosslinked polydiallylmethylamine (Example 6) wassuspended in 100 mL in a 500 mL 3-necked round-bottomed flask ofdeionized water. The polymer swelled significantly and was stirred witha mechanical stirrer. To this swollen gel, was added 32 g1-bromotetradecane dissolved in 100 mL ethanol, and the reaction mixturewas stirred for 10 minutes. 2 g 50% aqueous sodium hydroxide was thenadded and the reaction mixture was stirred at room temperature for 40minutes followed by heating to 75° C. for 1 hr. 1 g NaOH solution wasthen added followed by an additional 1 g of NaOH solution after another1.5 hr (the base addition was such as to maintain the pH between 10 to12). The reaction mixture was stirred at 75° C. for an additional 18hours after which time the heating was discontinued. After cooling to30° C., 2 mL concentrated HCl was added and the mixture was stirred for30 minutes. The polymer was filtered and washed with 500 mL deionizedwater followed by 500 mL methanol. Polymer particles were suspended in300 mL methanol and stirred for 40 minutes. After removing the solventby filtration, the polymer was suspended in 500 mL of 2M NaCl solutionand stirred for an additional 40 minutes. The polymer was filtered andthis process of NaCl treatment was repeated twice. The filtered polymercake was then washed with 500 mL deionized water and suspended in 500 mLdeionized water. After stirring for 30 minutes the polymer was filteredand resuspended in 500 mL deionized water and the suspension was stirredfor 30 minutes. 1 mL concentrated HCl was then added to the suspension,which was stirred for another 55 minutes. The polymer was then filteredand dried at 60° C. in a forced air oven, yielding 22 g of the alkylatedpolymer. The polymer was ground and passed through a 140 mesh sieve.

Example 15 Alkylation of Crosslinked Poly(diallylmethylamine) with1-Bromooctane

10 g of 4.5% crosslinked poly(diallylmethylamine) (Example 7) wassuspended in 100 mL in a 500 mL 3-necked round bottom flask of deionizedwater. The polymer swelled significantly and was stirred with amechanical stirrer. To this swollen gel, was added 23 g 1-bromooctanedissolved in 100 mL ethanol and the reaction mixture was stirred for 10minutes. 2 g of 50% aqueous sodium hydroxide was then added and thereaction mixture was stirred at room temperature for 40 minutes,followed by heating to 75° C. for 1 hr. 1 g NaOH solution was thenadded, followed by an additional 1 g of NaOH solution after another 1.5hr. The reaction mixture was allowed to stir at 75° C. for an additional18 hours after which time the heating was discontinued. After cooling to30° C., 2 mL concentrated HCl was added and stirring was continued for30 minutes. The polymer was filtered and washed with 500 mL deionizedwater followed by 500 mL methanol. Polymer particles were suspended in300 mL methanol and stirred for 40 minutes. After removing the solventby filtration, the polymer was suspended in 500 mL 2M NaCl solution andthe suspension was stirred for 40 minutes. The polymer was filtered andthis process of NaCl treatment was repeated twice. The filtered polymercake was washed with 500 mL deionized water and suspended in 500 mLdeionized water. After stirring for 30 minutes the polymer was filtered,resuspended in 500 mL deionized water, and stirred for 30 minutes. 1 mLconcentrated HCl was added to the suspension and stirred for 35 minutes.The polymer was then filtered and dried at 60° C. in a forced air oven,yielding 15.8 g of the alkylated polymer. The polymer was ground andpassed through a 140 mesh sieve.

Example 16 Alkylation of Crosslinked Poly(diallylmethylamine) with1-Bromohexane

10 g of 4.5% crosslinked poly(diallylmethylamine) (Example 6) taken in a500 mL 3-necked round bottom flask was suspended in 100 mL deionizedwater. The polymer swelled significantly and was stirred with amechanical stirrer. To this swollen gel was added, 19 g 1-bromodecanedissolved in 100 mL ethanol was added and the reaction mixture wasstirred for 10 minutes. 2 g of 50% aqueous sodium hydroxide was thenadded and the reaction mixture was stirred at room temperature for 40minutes, followed by heating to 75° C. for 1 hr. 1 g NaOH solution wasthen added followed by an additional 1 g of NaOH solution after another1.5 hr. The reaction mixture was stirred at 75° C. for an additional 18hours after which time the heating was discontinued. After cooling to30° C., 2 mL concentrated HCl was added and the mixture was stirred for30 minutes. The pH of the medium at this point was 2.0. The polymer wasfiltered and washed with 500 mL deionized water followed by 500 mLmethanol. The polymer particles were suspended in 300 mL methanol andstirred for 40 minutes. After removing the solvent by filtration, thepolymer was suspended in 500 mL of 2 M NaCl solution and the suspensionwas stirred for 40 minutes. The polymer was filtered and this process ofNaCl treatment was repeated twice. The filtered polymer cake was washedwith 500 mL deionized water and suspended in 500 mL deionized water.After stirring for 30 minutes, the polymer was filtered, resuspended in500 mL deionized water and stirred for 30 minutes. 1 mL concentrated HClwas added to the suspension, which was stirred for 35 minutes. Thepolymer was then filtered and dried at 60° C. in a forced air oven,yielding 13.7 g of the alkylated polymer. The polymer was ground andpassed through a 140 mesh sieve.

Example 17 Synthesis of Quaternized N-alkyl diallylmethylammonium Salts

Synthesis of N-decyldiallylmethylammonium bromide.

Diallylmethylamine (33.3 g) and 1-bromodecane (66.6 g) were dissolved in100 mL methanol and the reaction mixture was stirred at 65° C. for 48hours. After cooling to room temperature, the methanol was removed underreduced pressure. The residual viscous oil was precipitated into 800 mLdry ether with rapid stirring. The ether layer was decanted and theresidue was again treated with 500 mL dry ether. After stirring for 15minutes the solvent was removed and the oily residue was dried undervacuum at 35° C. for 48 hours, yielding 78 g of the product.

Synthesis of N-(N,N-dimethyl-N-dodecylammonio)propyldiallylmethylammonium chloride bromide

A mixture of 22 g diallylmethylamine and 74 g3-chloropropyldodecyldimethylammonium bromide were dissolved in 100 mLmethanol and the reaction mixture was stirred at 65° C. for 48 hours.The progress of the reaction was monitored by the disappearance of thedialllymethylamine by thin layer chromatography (TLC). After cooling toroom temperature, the solvent was removed under reduced pressure. Theresidual viscous oil was precipitated into 800 mL dry ether with rapidstirring. The ether layer was decanted and the residue was again treatedwith 500 mL dry ether. After stirring for 15 minutes the solvent wasremoved and the oily residue was dried under vacuum at 35° C. for 48hours, yielding 70 g of the product.

Synthesis ofN-(N,N-dimethyl-N-dodecylammonio)butyl-diallylmethylammonium chloridebromide

A mixture of 22 g diallylmethylamine and 75 g4-chlorobutyldimethyldodecylammonium bromide were dissolved in 100 mLmethanol and the reaction mixture was stirred at 65° C. for 48 hours.The progress of the reaction was monitored by the disappearance of thediallylmethylamine by thin layer chromatography (TLC). After cooling toroom temperature, the solvent was removed under reduced pressure. Theresidual viscous oil was precipitated into 800 mL dry ether with rapidstirring. The ether layer was decanted and the residue was again treatedwith 500 mL dry ether. After stirring for 15 minutes the solvent wasremoved and the oily residue was dried under vacuum at 35° C. for 48hours, yielding 65 g of the product.

Synthesis of Poly(N-decyldiallylmethylammonium bromide) crosslinked withmethylenebis(acrylamide)

25 g N-decyldiallylmethylammonium bromide, 3 gN,N-methylenebisa-crylamide and 300 mg2,2′-azobis(2-amidinopropane)dihydrochloride were dissolved in 100 mLdeionized water. The solution was bubbled with a slow stream of nitrogenfor 30 minutes then heated to 70° C. with stirring. After 2 hr, thereaction mixture turned cloudy with formation of a suspension. Themixture was kept at 70° C. for a period of 18 hours and then allowed tocool. The suspension was centrifuged. The residue dispersed in 200 mLdeionized water, stirred for 30 minutes and centrifuged. After removalof the supernatant, the residue was suspended in 200 mL methanol,stirred for 30 minutes and centrifuged. The residue was suspended in 300mL methanol and the suspension was refluxed for 1 hr. After cooling toroom temperature, the suspension was filtered and the white solid wasdried at 60° C. for 24 hr to yield 10 g of the polymer. The polymer wasground and passed through 140 mesh sieve.

Example 19 Synthesis of Crosslinked Poly(diallylammoniumchloride-co-sulfur dioxide) Copolymer

111 g of a 20% solution of copoly(diallylmethyl-ammoniumchloride-co-sulfur dioxide) (PAS-92, obtained from Nitto Boseki Co.,Japan) was treated with 2.2 g solid NaOH with stirring. The solutionturned cloudy and phase separation occurred. The bottom viscous layerwas separated from the top layer and the former was diluted with 20 mLwater. To this solution, 0.6 mL epichlorohydrin was added and thereaction mixture was allowed to stir for 2 hr. The reaction mediumslowly became increasingly viscous and was left at room temperature for48 hours, during which period it turned into a gel. The resultingpolymer gel was broken into smaller pieces and was dispersed in 1 literdeionized water. The suspension was stirred for 1 hr and filtered. Theswollen polymer particles were resuspended in 800 mL deionized water andstirred for 1.5 hr. The polymer particles were then filtered and driedin a forced air oven at 60° C. to yield 16 g of polymer. The driedpolymer was ground and passed through a 10 mesh sieve.

Example 20 Alkylation of 6% CrosslinkedCopoly(diallylmethylamine-co-sulfur dioxide) with 1-bromodecane

The polymer (5 g) of Example 20 was placed in a 500 mL 3-necked roundbottom flask and suspended in 100 mL deionized water. The polymerswelled significantly and was stirred with a mechanical stirrer. To thisswollen gel, a solution of 18 g 1-bromodecane in 100 mL ethanol wasadded and the reaction mixture stirred for 10 minutes. Subsequently, 2 g50% aqueous sodium hydroxide was added and the reaction mixture wasstirred at room temperature for 30 minutes followed by heating to 75° C.After 1 hr, 0.5 g NaOH solution was added followed by an additional 0.5g of NaOH solution after another 1.5 hr. The reaction mixture wasallowed to stir at 75° C. for an additional 18 hr after which time theheating was discontinued. After cooling to 30° C., 2 mL concentrated HClwas added and the mixture was stirred for 30 minutes. The pH of themedium dropped to 1.2. The polymer was filtered off and washed with 500mL deionized water and 500 mL methanol. Polymer particles were suspendedin 300 mL methanol and stirred for 40 minutes. After removing thesolvent by filtration, the polymer was suspended in 500 mL 2M NaClsolution and stirred for 40 minutes. The suspension was filtered and theNaCl treatment was repeated two more times. The filtered polymer cakewas washed with 500 mL deionized water and suspended in 500 mL deionizedwater. After stirring for 30 minutes it was filtered and resuspended in500 mL deionized water and stirred for 30 minutes. 1 mL of concentratedHCl was added to the suspension and the suspension was stirred for 35minutes. The polymer was then filtered and dried at 60° C. in a forcedair oven, yielding 9.1 g of the alkylated polymer. The polymer wasground and passed through a 140 mesh sieve.

Example 21 Alkylation of Crosslinked Copoly(diallylmethylamine-co-sulfurdioxide) with (3-chloropropyl)-dimethyldodecylammonium bromide

To a mixture of 5 g of the polymer of Example 20 and 30 g(3-chloropropyl)dimethyldodecylammonium bromide in a 500 mL 3-neckedround bottom flask was added 150 mL deionized water. The resultingmixture was stirred with a mechanical stirrer. 2 g of 50% aqueous sodiumhydroxide was added and the reaction mixture was stirred at roomtemperature for 30 minutes, followed by heating to 75° C. for 1 hr. NaOHsolution (0.5 g) was added, followed by an additional 0.5 g of NaOHsolution after another 1.5 hr. The reaction mixture was allowed to stirat 75° C. for an additional 18 hr after which time the heating wasdiscontinued. After cooling to 30° C., 2 mL concentrated HCl was addedand the mixture was stirred for 30 minutes. The pH of the medium droppedto 2.8. The polymer was filtered off and washed with 500 mL deionizedwater and 500 mL methanol. Polymer particles were then suspended in 300mL methanol and the suspension was stirred for 40 minutes. The polymerwas isolated by filtration and then suspended in 500 mL 2M NaClsolution. The suspension was stirred for 40 minutes. The polymer wasfiltered off and this NaCl treatment was repeated two more times. Thefiltered polymer cake was washed with 500 mL deionized water and thensuspended in 500 mL deionized water. After stirring for 30 minutes thepolymer was filtered off and resuspended in 500 mL deionized water. Thesuspension was stirred for 30 minutes. 1 mL concentrated HCl was addedto the suspension and the suspension was stirred for 35 minutes. Thepolymer was then filtered and dried at 60° C. in a forced air oven,yielding 11.4 g of the alkylated polymer. The polymer was ground andpassed through a 140 mesh sieve.

Example 22 Preparation of Poly(diallylammonium chloride)

100 g diallylamine and 100 mL deionized water were placed in a 1 literbeaker and the mixture was allowed to stir. To this stirred mixture, 37%aqueous HCl was added slowly with concurrent measurement of pH. When thepH of the solution dropped below 7, addition of acid stopped. Thesolution was extracted with 600 mL diethyl ether. To the aqueoussolution, 3 g 2,2′-azobis(2-amidinopropane) dihydrochloride was addedand the solution was bubbled with nitrogen gas for 45 minutes. Thesolution was then heated to 70° C. for 48 hr, after which time thereaction mixture has turned viscous. Heating was discontinued and, aftercooling to room temperature, 315 g of polymer solution was obtained.

Example 23 Synthesis of insoluble crosslinked polydiallylamine

The polydiallylammonium chloride solution of Example 23 (150 g) wasdiluted with 50 mL deionized water. Solid NaOH (6.75 g) was added to thepolymer solution with stirring. The reaction mixture was stirred untilthe NaOH has dissolved and temperature of the solution had dropped tobelow 30° C. To this partially neutralized polymer solution,epichlorohydrin (1.2 mL) was added and stirring was continued. Thereaction medium slowly became increasingly viscous and after about 50minutes it gelled and the stirring stopped. This gelled polymer was leftat room temperature for an additional 48 hr to yield a semi-brittlepolymer slab. The polymer slab was broken into smaller pieces and wasdispersed in 1 L deionized water. The resulting suspension was stirredfor 1.5 hr and then filtered. The swollen polymer particles wereresuspended in 1 L deionized water and the suspension was stirred for 40minutes. The polymer particles were filtered off and dried in a forcedair oven at 60° C. to yield 56 g of pale white solid polymer. The driedpolymer was ground and passed through a 10 mesh sieve.

Example 24 Alkylation of Crosslinked Polydiallylamine with1-bromododecane

The ground polymer of Example 23 (5 g) was placed in a 500 mL 3-neckedround-bottomed flask and suspended in 100 mL deionized water and thesuspension was stirred with a mechanical stirrer. To this swollen gel, asolution of 15 g 1-bromodecane in 100 mL ethanol was added and thereaction mixture was stirred for 10 minutes. 2 g 50% aqueous sodiumhydroxide was then added and the reaction mixture was stirred at roomtemperature for 40 minutes followed by heating to 75° C. Subsequently,an additional 4 g 50% NaOH was added in a 1 g batch at an interval of1.5 hr (the base addition maintained a pH between 10 to 12). Thereaction mixture was allowed to stir at 75° C. for a total period of 20hr. After cooling to 30° C., 2 mL concentrated HCl was added and themixture was stirred for 30 minutes. The polymer was filtered off andwashed with 500 mL deionized water and 500 mL methanol. The filteredpolymer particles were slurried in methanol (400 mL), stirred for 40minutes and reisolated by filtration. This process was then repeated.The polymer was suspended in 500 mL 2M NaCl solution and the suspensionwas stirred for 40 minutes. The polymer was filtered off and this NaCltreatment was repeated two more times. The fitered polymer cake waswashed with 500 mL deionized water and suspended in 500 mL deionizedwater. After stirring the suspension for 30 minutes, the polymer wasfiltered off and resuspended in 500 mL deionized water. The resultingsuspension was stirred for 30 minutes. 1 mL concentrated HCl was addedto the suspension, which was then stirred for 35 minutes. The pH of thesuspension was found to be 2.2. The polymer was then filtered off anddried at 60° C. in a forced air oven, yielding 13.3 g of the alkylatedpolymer as a pale white solid. The polymer was ground and passed througha 140 mesh sieve.

Example 25 Alkylation of Crosslinked Polydiallylamine with(3-chloropropyl)dimethyldodecylammonium bromide

A mixture of 5 g of the crosslinked polymer gel of Example 23 and 28 g(3-chloropropyl)dimethyl-dodecylammonium bromide was dispersed in 150 nLdeionized water and the suspension was stirred. To this suspension 2 g50% NaOH was added and the mixture was stirred for 15 minutes. Themixture was then heated with stirring to 75° C. An additional 4 g 50%NaOH was added in 1 g batches at 1.5 hr intervals (the base addition wassuch as to maintain the pH between 10 to 12). After stirring at 75° C.for a total period of 18 hr, the reaction mixture was allowed to cool.After cooling to 30° C., 2 mL concentrated HCl was added and the mixturewas stirred for 30 minutes. The polymer particles were filtered off andwashed with 200 mL methanol. The filtered polymer particles weresuspended twice in methanol (400 mL) and the suspension was stirred for40 minutes. This process was repeated. After removing the polymer byfiltration, the polymer was suspended in 500 mL 2M NaCl solution and thesuspension was stirred for 40 minutes. This NaCl treatment was repeatedtwice and the filtered polymer was suspended in 500 mL deionized waer.The mixture was stirred for an additional 45 minutes, filtered,resuspended in 400 mL deionized water and stirred for another 40minutes. To this suspension, 1 mL concentrated HCl was added and themixture was stirred for 20 minutes. The polymer was filtered off anddried in a forced air oven at 60° C., yielding 13.2 g of alkylatedpolymer as a light yellow solid which was ground and passed through a140 mesh sieve.

Example 26 Alkylation of Crosslinked Poly(diallylmethylamine) with1-bromooctane

The 3% crosslinked poly(diallylmethylamine) of Example 6 (5 g) was takenin a 500 mL 3-necked round-bottomed flask and suspended in 110 mLdeionized water. The polymer swelled significantly and was stirred witha mechanical stirrer. To this swollen gel, a solution of 11.1 g1-bromooctane in 50 mL ethanol was added and the reaction mixture wasstirred for 10 minutes. 1 g 50% aqueous sodium hydroxide was then addedand the reaction mixture was stirred at room temperature for 40 minutesfollowed by heating to 75° C. for 1.5 hr. 1 g NaOH solution was added,and the reaction mixture was allowed to stir at 75° C. for an additional18 hr. After the mixture had cooled to 30° C., 2.5 mL concentrated HClwas added and the mixture was stirred for 30 minutes. The polymer wasfiltered and washed with 300 mL deionized water and 300 mL methanol.Polymer particles were suspended in 300 mL methanol and the suspensionwas stirred for 40 minutes. After removing the polymer by filtration,the polymer was suspended in 300 mL 2 M NaCl solution and the suspensionwas stirred for 40 minutes. The polymer was filtered off and this NaCltreatment was repeated two more times. The filtered polymer cake waswashed with 400 mL deionized water, then suspended in 400 mL deionizedwater. After the suspension was stirred for 30 minutes, it was filteredand the polymer was resuspended in 400 mL deionized water and thissuspension was stirred for an additional 30 minutes. 1 mL concentratedHCl was added to the suspension, which was then stirred for 30 minutes.The polymer was filtered and dried at 60° C. in a forced air oven,yielding 7.0 g of the alkylated polymer as a pale white solid. Thepolymer was ground and passed through a 140 mesh sieve.

Example 27 Alkylation of Crosslinked Poly(diallylmethylamine) with1-bromotetradecane

The 3% crosslinked poly(diallylmethylamine) of Example 6 (5 g) was takenin a 500 mL 3-necked round bottomed flask and suspended in 100 mLdeionized water. The polymer swelled significantly and was stirred witha mechanical stirrer. To this swollen gel, 16 g 1-bromotetradecanedissolved in 40 mL ethanol was added and the reaction mixture wasstirred for 10 minutes. 1 g 50% aqueous sodium hydroxide was then addedand the reaction mixture was stirred at room temperature for 40 minutesfollowed by heating to 75° C. for 1.5 hr. 1 g NaOH solution was thenadded and the reaction mixture was stirred at 75° C. for additional 18hr. After cooling to 30° C., 2.5 mL concentrated HCl was added and themixture was stirred for 30 minutes. The polymer was filtered and washedwith 300 mL deionized water and 300 mL methanol. Polymer particles weresuspended in 300 mL methanol and the suspension was stirred for 40minutes. After removing the polymer by filtration, the polymer wassuspended in 300 mL 2M NaCl solution and the suspension was stirred for40 minutes. The polymer was filtered off and this NaCl treatment wasrepeated two more times. The filtered polymer cake was washed with 400mL deionized water and suspended in 400 mL deionized water. Afterstirring for 30 minutes the suspension was filtered and the polymer wasresuspended in 400 mL deionized water. This suspension was stirred foran additional 30 minutes. 1 mL concentrated HCl was then added to thesuspension and stirring continued for 30 minutes. The polymer wasfiltered off and dried at 60° C. in a forced air oven, yielding 9.0 g ofthe alkylated polymer as a pale white solid. The polymer was ground andpassed through a 140 mesh sieve.

Example 28 Alkylation of Crosslinked Poly(diallylmethylamine) with(3-chloropropyl)dimethyloctadecylammonium bromide

(3-Chloropropyl)dimethyloctadecylammonium bromide was prepared by thegeneral method of Example 10 starting with dimethyloctadecylamine. Amixture of the crosslinked polymer gel of Example 6 and 35 g(3-chloropropyl)dimethyloctadecylammonium bromide was dispersed in 150mL deionized water and the mixture was heated to 70° C. with stirringfor 15 minutes. 2 g 50% aqueous solution of NaOH and 50 mL ethanol werethen added to the reaction mixture. After 2 hr, 0.5 g NaOH solution wasadded and the reaction mixture was stirred at 70° C. for 20 hr. When thereaction mixture had cooled to 30° C., 2 mL concentrated HCl was addedand the mixture was stirred for another 20 minutes. The polymer wasfiltered off and washed with 200 mL deionized water and 200 mL methanol.The filtered polymer particles were dispersed in 500 mL methanol,stirred for another 30 minutes and then filtered. This process wasrepeated one more time and the filtered polymer was suspended in 300 mL2M NaCl solution. The resulting suspension was stirred for another 45minutes and filtered. After repeating the NaCl treatment twice, thefiltered polymer was suspended in 400 mL deionized water. The mixturewas stirred for 30 minutes, filtered, and the polymer was resuspended in400 mL deionized water. The suspension was stirred for an additional 40minutes. To this suspension was added 1 mL concentrated HCl and themixture was stirred for 20 minutes. The polymer was filtered and driedin a forced air oven at 60° C., yielding 10.7 g alkylated polymer as apale white solid which was ground and passed through a 140 mesh sieve.

Example 29 Alkylation of Crosslinked Poly(diallylmethylamine) with(3-Chloropropyl)dodecylpyrrolidiniumammonium bromide

Synthesis of (3-chloropropyl)dodecylpyrrolidinium bromide

47 g pyrrolidine, 149.5 g 1-bromododecane and 83 g potassium carbonatewere added to 560 mL acetone. The reaction mixture was heated at 55° C.for 24 hr, then filtered. Solvent was removed from the filtrate,yielding 92 g N-dodecylpyrrolidine. 80 g N-dodecylpyrrolidine and 52.6 g1-bromo-3-chloropropane were dissolved in 133 mL methanol and thereaction mixture was heated at 65° C. for 18 hr. After cooling to roomtemperature, methanol was removed under reduced pressure. The residuewas poured into 2 L diethylether with stirring and the mixture wasallowed to stand for another 6 hr. The white precipitate thus formed wasfiltered and was dried at 40° C. under a vacuum for 24 hr yielding 85 g(3-chloropropyl)dodecylpyrrolidinium bromide as a white solid.

Alkylation of Crosslinked Poly(diallylmethylamine) with (3-chloropropyl)dodecylpyrrolidinium bromide

The 3% crosslinked poly(diallylmethylamine) of Example 7 (5 g) and 30 g(3-chloropropyl)dodecyl-pyrrolidinium bromide were dispersed in 150 mLdeionized water and the mixture was heated to 70° C. with stirring.After stirring at 70° C. for 15 minutes, 2 g 50% aqueous NaOH solutionwas added to the reaction mixture. After 2 hr, 1 g NaOH solution wasadded and the reaction mixture was allowed to stir at 70° C. for 20 hr.The reaction mixture was then allowed to cool to 30° C. 2 mLconcentrated HCl was then added and the mixture was stirred for 20minutes. The polymer was filtered off and washed with 200 mL deionizedwater and 200 mL methanol. The polymer particles were dispersed in 500mL methanol and the suspension was stirred for 30 minutes and thenfiltered. This process was repeated one more time and the filteredpolymer was suspended in 300 mL 2M NaCl solution. The resultingsuspension was stirred for 45 minutes and filtered. After repeating thisNaCl treatment twice, the filtered polymer was suspended in 400 mLdeionized water. The mixture was stirred for 30 minutes, filtered,resuspended in 400 mL deionized water and stirred for an additional 40minutes. To this polymer suspension was added 1 mL concentrated HCl andstirring continued for an additional 20 minutes. The polymer wasfiltered off and dried in a forced air oven at 60° C., yielding 13 galkylated polymer as a pale white solid which was ground and passedthrough a 140 mesh sieve.

Example 30 Alkylation of Crosslinked Poly(diallylmethylamine) with(3-Chloropropyl)dodecylpiperidinium bromide

Synthesis of (3-chloropropyl)decylpiperidinium bromide

N-decylpiperidine was synthesized by reacting 45.7 g piperidine with118.7 g 1-bromodecane in 237 mL acetone in the presence of 74 gpotassium carbonate. After refluxing this reaction mixture at 55° C. for24 hr, it was filtered and acetone was removed from the filtrate toyield 61 g N-decylpiperidine. 5 g N-decylpiperidine and 42 g1-bromo-3-chloropropane were dissolved in 50 mL methanol and thereaction mixture was heated at 65° C. for 18 hr. After cooling to roomtemperature, methanol was removed under reduced pressure. The residuewas poured into 2 L tert.butylmethyl ether with stirring and then themixture was allowed to stand for 6 hr. The white precipitate thus formedwas filtered and was dried at 40° C. under vacuum for 24 hr yielding 68g (3-chloropropyl)decylpiperidinium bromide as a light yellow solid.

Alkylation of Crosslinked Poly(diallylmethylamine) with (3-chloropropyl)decylpiperidinium bromide

The 3% crosslinked poly(diallylmethylamine) of Example 6 (5 g) and 32 g(3-chloropropyl) decylpiperidiniumammonium bromide were dispersed in 150mL deionized water and the reaction mixture was heated to 70° C. withstirring for 15 minutes. 2 g 50% aqueous solution of NaOH was then addedto the reaction mixture. After 2 hr, 1 g NaOH solution was added and thereaction mixture was allowed to stir at 70° C. for 20 hr. When thereaction mixture had cooled to 30° C., 2 mL concentrated HCl was addedand the mixture was stirred for 20 minutes. The polymer was filtered offand washed with 200 mL deionized water and 200 mL methanol. The polymerparticles were dispersed in 500 mL methanol and the suspension wasstirred for an additional 30 minutes, then filtered. This process wasrepeated once and the polymer was suspended in 300 mL 2M NaCl solution.The suspension was stirred for 45 minutes and filtered. After repeatingthis NaCl treatment twice, the filtered polymer was suspended in 400 mLdeionized water. The mixture was stirred for 30 minutes, filtered,resuspended in 400 mL deionized water and the suspension was stirred for40 minutes. To this polymer suspension was added 1 mL concentrated HCland the mixture was stirred for 20 minutes. The polymer was filtered offand dried in a forced air oven at 60° C., yielding 13.2 g alkylatedpolymer as a pale white solid which was ground and passed through a 140mesh sieve.

Example 31 Alkylation of Crosslinked Poly(diallylmethylamine) with(4-Chlorobutyl)diethyldecylammonium bromide

(4-Chlorobutyl)diethyldecylammonium bromide was prepared by the generalmethod of Example 10 using 4-chloro-1-bromobutane and decyldiethylamine.The 3% crosslinked poly(diallylmethylamine) of Example 6 (5 g) and 22 g(4-chlorobutyl) diethyldecylammonium bromide were dispersed in 150 mLdeionized water and the resulting mixture was heated to 70° C. withstirring for 15 minutes. 2 g 50% aqueous solution of NaOH was then addedto the reaction mixture. After 2 hr, 0.5 g NaOH solution was added andthe reaction mixture was allowed to stir at 70° C. for 20 hr. When thereaction mixture had cooled to 30° C., 2 mL concentrated HCl was addedand the mixture was stirred for an additional 20 minutes. The polymerwas filtered off and washed with 200 mL deionized water and 200 mLmethanol. The polymer particles were dispersed in 500 mL methanol andthe suspension was stirred for 30 minutes and then filtered. Thisprocess was repeated once and the filtered polymer was suspended in 300mL 2M NaCl solution. The suspension was stirred for an additional 45minutes and filtered. After repeating this NaCl treatment twice, thefiltered polymer was suspended in 400 mL deionized water and the mixturewas stirred for an additional 40 minutes. To this polymer suspension wasadded 1 mL concentrated HCl and the mixture was stirred for 20 minutes.The polymer was filtered off and dried in a forced air oven at 60° C.,yielding 10.6 g alkylated polymer as a pale white solid which was groundand passed through a 140 mesh sieve.

Example 32 Alkylation of Crosslinked Poly(diallylmethylamine) withVarying Amounts of (3-Chloropropyl)dimethyl-dodecylammonium bromide

This example illustrates alkylation of the 3% crosslinkedpoly(diallylmethylamine) of Example 6 with different amounts of(3-chloropropyl)dimethyldodecylammonium bromide. For this purpose, thepolymer was treated with varying mole fractions of the alkylating agent(1.0, 0.75, 0.50, 0.25 and 0.10) via the general procedure described inExample 9. Table 2 summarizes amounts of (3-chloropropyl)dimethyldodecylammonium bromide used to obtain polymers of varyingdegree of alkylation and yield of alkylated polymer per gram of the 3%crosslinked poly(diallylmethylamine). This g/g yield is a measure of thedegree of alkylation of the polymer.

TABLE 2 Results of the alkylation of 3% crosslinkedpoly(diallylmethylamine) with varying amounts of(3-chloropropyl)dimethyldodecylammonium bromide (C₁₂QC₃C₁Br). PolymerAlkylating Mole frctn of Yield of used (g) agent used (g) alkylatingagent alkylated Yield (g/g) 5.0 14.25 1.0 11.3 2.3 5.0 10.7 0.75 8.3 1.75.0 7.1 0.50 7.0 1.40 5.0 3.6 0.25 6 1.20 5.0 1.40 0.10 5.1 1.02

Example 33 Synthesis of 1,4-butanediol diglycidyl ether CrosslinkedPoly(diallylmethylamine)

33.2 g the 60% solution of poly(diallylmethylamine) (PAS-M-1, Lot#51017)was diluted with 68 mL D.I. water. While stirring, 2.8 g NaOH was addedto the polymer solution. The reaction mixture was allowed to stir untilall NaOH had dissolved. When the temperature of the solution has droppedto below 30° C., 1.25 g 1,4-butanediol diglycidyl ether was added andstirring continued. The reaction medium slowly became increasinglyviscous and after about 45 minutes it gelled and the stirring wasstopped. The polymer gel was left at room temperature for an additional48 hours. The polymer slab was broken into smaller pieces and wasdispersed in 300 mL D.I. water. The suspension was stirred for 30minutes and was filtered. The swollen polymer particles were resuspendedin 400 mL D.I. water, stirred for 1 hr and filtered. This process wasrepeated twice more. The filtered polymer (swollen gel) was dried in aforced air oven at 60° C. to yield 15 g of the product.

Example 34 Alkylation of 1,4-butanediol diglycidyl ether CrosslinkedPoly(diallyl-methylamine) with 1-bromodecane

5 g of the ground polymer (Example 33) was placed in a 500 mL 3-neckedround-bottomed flask was suspended in 100 mL D.I. water. The polymerswelled significantly and was stirred with a mechanical stirrer. To thisswollen gel, 12 g 1-bromodecane dissolved in 100 mL ethanol was addedand the reaction mixture stirred for 10 minutes. Subsequently, 1 g 50%aqueous sodium hydroxide was added and the reaction mixture was stirredat room temperature for 40 minutes followed by an additional 0.5 g ofNaOH solution after another 1.5 hr (the base addition was such as tomaintain the pH between 10 and 12). The reaction mixture was allowed tostir at 75° C. for an additional 18 hrs after which time heating wasdiscontinued. After cooling to 30° C., 2 mL concentrated HCl was addedand stirring for 30 minutes continued. The pH of the suspension droppedto 1.8. The polymer was filtered and washed with 250 mL D.I. waterfollowed by 250 mL methanol. Polymer particles were suspended in 300 mLmethanol and stirred for 40 minutes. After removing the solvent byfiltration, the polymer was suspended in 250 mL 2M NaCl solution andstirred for an additional 40 minutes. It was filtered and this processof NaCl treatment was repeated two more times. The filtered polymer cakewas washed with 250 mL D.I. water and suspended in 250 mL D.I. water.After stirring for 30 minutes it was filtered and resuspended in 400 mLD.I. water and stirred for an additional 30 minutes. 2 mL conc. HCl wasadded to the suspension and stirred for another 15 minutes. The pH ofthe suspension was found to be 2.10. After stirring for an additional 20minutes, the polymer was filtered and dried at 60° C. in a forced airoven yielding 9 g of the alkylated polymer as a pale white solid. Thepolymer was ground and passed through a 140 mesh sieve.

Example 35 Reaction of poly(diallylmethylamine) with(4-chlorobutyl)dimethyldodecyl ammonium bromide

A solution of poly(diallylmethylamine) hydro-chloride (8.38 g of a 60%polymer solution in water), NaOH (5.5 g of a 50% NaOH solution inwater), deionized water (150 mL) and (4-chlorobutyl)dimethyldodecylammonium bromide (26.2 g) was heated to 75° C. for 24 hours. Aftercooling to room temperature, the mixture was filtered. The solid waswashed on the funnel with deionized water (1.5 L). The solid wassuspended again in 2 M NaCl (1.0 L), stirred for 30 minutes, and thenfiltered. The solid was suspended again in 2 M NaCl (1.0 L), stirred for30 minutes, and then filtered. The solid was suspended again in 2 M NaCl(1.0 L), stirred for 30 minutes, and then filtered. The solid was washedon the funnel with deionized water (2.0 L). The solid was suspended indeionized water (1.0 L), and concentrated HCl (1.4 mL) was added to thissuspension. After stirring 1 hour, this suspension was filtered. Thematerial was dried in a forced air oven at 60° C. for 24 hours to afford19.1 g of product.

Example 36 Reaction of poly(diallylmethylamine) with 1-bromodecane

To a solution of poly(diallylmethylamine) hydro-chloride (16.7 g of a60% polymer solution in water), NaOH (5.5 g of a 50% NaOH solution inwater), deionized water (100 mL), and ethyl alcohol (100 mL) was added1-bromodecane (44.4 g). This solution was then heated to 75° C. for 24hours. After the first 2 hours of heating, NaOH (1.0 g of a 50% NaOHsolution in water) was added. After cooling to room temperature, themixture was evaporated on a rotary evaporator to remove the ethylalcohol. Water (500 mL) was added to the mixture, and the mixture wasfiltered. The solid was washed on the funnel with deionized water (1.0L). The solid was suspended in 2M NaCl (1.0 L), stirred for 30 minutes,and then filtered. The solid was suspended again in 2 M NaCl (1.0 L),stirred for 30 minutes, and then filtered. The solid was suspended againin 2 M NaCl (1.0 L), stirred for 30 minutes, and then filtered. Thesolid was washed on the funnel with deionized water (2.0 L). The solidwas suspended in deionized water (1.0 L) and concentrated HCl (2.4 mL)was added to this suspension, and after stirring 1 hour, this suspensionwas filtered. The material was dried in a forced air oven at 60° C. for24 hours to afford 20.8 g of product.

Example 37

A suspension of the product from Example 36 (5.01 g), methyl alcohol(100 mL), iodomethane (7.4 mL), and NaOH (1.0 g of a 50% NaOH solutionin water) was stirred at room temperature for 24 hours. After the first7 hours of reaction, iodomethane (7.4 mL) was added. After the 24 hourreaction period at room temperature, NaOH (1.0 g of a 50% NaOH solutionin water) was added, and the mixture was heated to 50° C. for 4 hours.After one hour of heating, NaOH was added (1.0 g of a 50% NaOH solutionin water). After the first 2.5 hours of heating (0.5 g of a 50% NaOHsolution in water), NaOH was again added. After cooling to roomtemperature, methyl alcohol (100 mL) was added to the mixture, and themixture was evaporated on a rotary evaporator to remove the methylalcohol. The solid was suspended in 2M NaCl (1.0 L), stirred for 30minutes, and then filtered. The solid was suspended again in 2M NaCl(1.0 L), stirred for 30 minutes, and then filtered. The solid wassuspended again in 2M NaCl (1.0 L), stirred for 30 minutes, and thenfiltered. The solid was washed on the funnel with deionized water (4.0L). The solid was suspended in deionized water (1.0 L) and concentratedHCl (50 drops) was added to this suspension, and after stirring 30minutes, this suspension was filtered. The material was dried in aforced air oven at 60° C. to afford 5.2 g of product.

Example 38

A suspension of the product from Example 35 (5.01 g), methyl alcohol(100 mL), iodomethane (7.0 mL), and NaOH (1.0 g of a 50% NaOH solutionin water) was stirred at room temperature for 24 hours. After 7 hours ofreaction, iodomethane (7.0 mL) was added. Following a 24 hour reactionperiod at room temperature, NaOH (1.0 g of a 50% NaOH solution in water)was added, and the mixture was heated to 50° C. for 4 hours. After thefirst hour of heating, NaOH was added (1.0 g of a 50% NaOH solution inwater). After 2.5 hours of heating, NaOH was again added (0.5 g of a 50%NaOH solution in water). After cooling to room temperature, methylalcohol (100 mL) was added to the mixture, and the mixture wasevaporated on a rotary evaporator to remove the methyl alcohol. Thesolid was suspended in 2M NaCl (1.0 L), stirred for 30 minutes, and thenfiltered. The solid was suspended again in 2M NaCl (1.0 L), stirred for30 minutes, and then filtered. The solid was suspended again in 2M NaCl(1.0 L), stirred for 30 minutes, and then filtered. The solid was washedon the funnel with deionized water (4.0 L). The solid was suspended indeionized water (1.0 L), and concentrated HCl (50 drops) was added tothis suspension. After stirring 30 minutes, this suspension wasfiltered. The material was dried in a forced air oven at 60° C. toafford 4.9 g of product.

Example 39 In Vivo Testing

The polymers produced in Examples 35–37 were tested in vivo, using thefollowing protocol. After a week of acclimation to the facility, theanimals were transferred to special cages that separate urine and feces.They were given only water for a 24 hour period in order to synchronizetheir urge for food as a drug. The food was presented for a 72 hourperiod. Fecal material was collected for 63 hours, from the hour 9 tohour 72 post presentation. The fecal material was freeze-dried toeliminate water from the material. It was pulverized with an amalgamatorto a uniform powder, and 1 g was placed in the extraction cell. Asolution of 80% methanol 100 mMol NaOH was used as the extractionsolvent. The extraction was accelerated by holding the sample andsolvent at 100° C. and 1500 psi for 5 minutes. The extraction wasevaporated and reconstituted in bovine calf serum. The concentration wasmultiplied by four times the volume of extract and expressed as theconcentration per gram of feces.

It is clear from the results shown in Table 3 that these sequestrantsare highly active in vivo, with efficacy far surpassing the commercialbile acid sequestrant cholestyramine.

TABLE 3 In Vivo Efficacy of Polymers of Examples 35–37 Bile AcidExcretion (μmole/g Polymer Dose (Percent in Diet) feces above control)None   0% 0 Cholestyramine  0.3% 1.7 0.60% 4.8 0.90% 6.3 1.20% 7.5Example 35 0.10% 1.40 Example 36 0.10% 3.7 Example 37 0.10% 2.5

Example 40

In a 5 mL three necked round bottom flask was taken 10 g of thecrosslinked poly(diallylmethylamine) of Example 6. To this was added 200mL of deionized water. While stirring, 2 g of 50% aqueous NaOH solutionwas added to this polymer suspension. After stirring for 15 minutes,13.6 g of 1-chlorodecane was added and the reaction mixture was heatedto 90° C. with stirring. After 1.5 hr of heating, 1.0 g of reagant ofthe NaOH solution was added to the reaction mixture followed by anadditional 0.5 g of the NaOH after another 2 hr. After stirring at 90°C. for a total period of 18 hr, the reaction mixture was allowed to coolto room temperature. Concentrated HCl (5 mL) was added to the reactionmixture and stirred for 30 minutes. The polymer was filtered and waswashed with 500 mL of methanol. The polymer particles were suspended in1 L of methanol, stirred for 30 minutes and filtered. After repeatingthis methanol washing once more, the polymer particles were suspended in1 L of deionized water. The suspension was stirred for 30 minutes andfiltered. The polymer particles were resuspended in 1 L of deionizedwater and stirred for 15 minutes. To this suspension was added 3 mL ofconcentrated HCl and the stirring continued for an additional 30minutes. The particles were filtered and dried in a forced air oven at60° C., yielding 16 g of the alkylated polymer as light yellowish solid.The polymer was ground and passed through a 140 mesh sieve.

Example 41

This Example illustrates the role of the reaction temperature duringalkylation of crosslinked of poly(diallylmethylamine) with1-chlorodecane. For this purpose, the alkylation reactions were carriedout at 70° C., 80° C., 90° and 100° C. The amount of 1-chlorodecane usedand the reaction time was kept unchanged for all the reactions. Yield ofthe alkylated polymer thus obtained at these reactions temperatures aresummarized in Table 4.

In a 500 mL three necked round bottomed flask was taken 10 g of thecrosslinked poly(diallylmethylamine) (Example 6). To this was added 200mL of deionized water. While stirring, 2 g of 50% aqueous NaOH solutionwas added to this polymer suspension. After stirring for 15 minutes,13.6 g of 1-chlorodecane was added and the reaction mixture heated tothe appropriate temperature with stirring. After 1.5 hr of heating, 1.0g of reagent of the NaOH solution was added to the reaction mixturefollowed by an additional 0.5 g of the NaOH after another 2 hr. Afterstirring at the appropriate temperature for a total period of 18 hr, thereaction mixture was allowed to cool to room temperature. ConcentratedHCl (5 mL) was added to the reaction mixture and stirred for 30 minutes.The polymer was filtered and was washed with 500 mL of methanol. Thepolymer particles were suspended in 1 L of methanol, stirred for 30minutes and filtered. After repeating this methanol washing once more,the polymer particles were suspended in 1 L of deionized water. Thesuspension was stirred for 30 minutes and filtered. The polymerparticles were resuspended in 1 L of deionized water and stirred for 15minutes. To this suspension was added 3 mL of concentrated HCl and thestirring continued for an additional 30 minutes. The particles werefiltered and dried in a forced air oven at 60° C. Yield of the alkylatedpolymers obtained at different reaction temperatures are summarized inTable 4. All the polymers were ground and passed through a 140 meshsieve.

TABLE 4 Results on the role of the reaction temperature on thealkylation of 4.5% epichlorohydrin crosslinked poly(diallylmethylaminewith 1-chlorodecane. Reaction 1-Chlorodecane used Temperature ProductPolymer used (g) (g) (° C.) Yield (g) 10 13.6 70 11.6 10 13.6 80 13.5 1013.6 90 16.0 10 13.6 100 17.0

Example 42

This Example illustrates the role of the amounts of the 1-chlorodecaneused in the alkylation of 4.5% epichlorohydrin crosslinkedpoly(diallylmethylamine) to prepare polymers with different degrees ofalkylation. For this purpose, the polymer was treated with varying molefractions of 1-chlorodecane (1.0, 0.5 and 0.25). All alkylationreactions were carried out at 90° C. for a period of 18 hr. Table 5summarizes the amounts of 1-chlorodecane used to obtain polymers ofvarying degrees of alkylation and the yield of the correspondingalkylated polymers.

In a 500 mL three necked round bottomed flask was taken 10 g of thecrosslinked poly(diallylmethylamine) (example 6). To this was added 200mL of deionized water. While stirring, 2 g of 50% aqueous NaOH solutionwas added to this polymer suspension. After stirring for 15 minutes,appropriate amount of 1-chlorodecane was added and the reaction mixtureheated to 90° C. with stirring. After 1.5 hr of heating, 1.0 g ofreagent of the NaOH solution was added to the reaction mixture followedby an additional 0.5 g of the NaOH after another 2 hr. After stirring at90° C. for a total period of 18 hr, the reaction mixture was allowed tocool to room temperature. Concentrated HCl (5 mL) was added to thereaction mixture and stirred for 30 minutes. The polymer was filteredand was washed with 500 mL of methanol. The polymer particles weresuspended in 1 L of methanol, stirred for 30 minutes and filtered. Afterrepeating this methanol washing once more, the polymer particles weresuspended in 1 L of deionized water. The suspension was stirred for 30minutes and filtered. The polymer particles were resuspended in 1 L ofdeionized water and stirred for 15 minutes. To this suspension wasstirred for 30 minutes. The particles were filtered and dried in aforced air oven at 60° C. Yield of the alkylated polymers obtained fordifferent alkylation levels are summarized in Table 5. All the polymerswere ground and passed through a 140 mesh sieve.

TABLE 5 Results of the alkylation of 4.5% epichlorohydrin crosslinkedpolydiallymethyl-amine with varying amounts of 1-chlorodecane. Polymer1-Chlorodecane used Reaction Product Yield used (g) (g) Temperature (°C.) (g) 10 3.4 90 12.2 10 6.8 90 14.5 10 10.2 90 15.7 10 13.6 90 16.0

Example 43

Non-crosslinked Polydiallylamine hydrochloride (PDA-HCl) andnon-crosslinked Poly(diallylmethylamine) hydrochloride (PDMA-HCl) werereacted with a variety of crosslinking agents and alkylating agents.Table 6 gives details of the crosslinking and alkylating agents,reaction conditions and yields (IPA=isopropyl alcohol;PDA=poly(diallylamine), PDMA=poly(diallylmethylamine)). The reactionsconditions are analogous to those described in Example 42 wherecrosslinked poly(diallylmethylamine) was reacted with 1-chlorodecane.

TABLE 6 Solvent Time Example Reactants (amount) (amount) Temperature(hr) Yield 43 PDMA.HCl (100.0 g of 60% ag H₂O 75° C. 18 88 soln),1-bromodecane (62.9 g), (600) mL epichlorohydrin (4.77 mL), NaOH (32.5 gof 50% aq soln) 44 PDMA.HCl (100.0 g of 60% aq IPA 75° C. 18 99 soln),1-bromodecane (62.9 g), (100 mL) 1,6-dibromohexane (9.37 mL), H₂O NaOH(5 addns of 6.5 g of 50% aq (500 mL) soln) 45 PDMA.HCl (100.0 g of 60%aq IPA 75° C. 18 92 soln), 1-bromodecane (62.9 g), (100 mL)epichlorohydrin (4.77 mL), NaOH H₂O (32.5 g of 50% ag soln) (500 mL) 46PDA.HCl (103.7 g of 52.3% aq IPA 75° C. 18 53 soln), 1-bromodecane (62.9g), (100 mL) epichlorohydrin (4.77 mL), NaOH (7 H₂O addns for a total of45 g of 50% aq (100 mL) soln) 47 PDA.HCl (103.7 g of 52.3% aq IPA 75° C.18 67 soln), 1-bromodecane (62.9 g), (100 mL) epichlorohydrin (4.77 mL),NaOH (90 g of 50% aq soln) 48 PDA.HCl (103.7 g of 52.3% aq IPA 75° C. 1862 soln), 1-bromodecane (62.9 g), (100 mL) epichlorohydrin (4.77 mL),NaOH (4 addns of 13.8 g of 50% aq soln) 49 PDA.HCl (103.7 g of 52.3% aqIPA 75° C. 18 64 soln), 1-bromodecane (62.9 g), (100 mL) epichlorohydrin(4.77 mL), NaOH H₂O (135.0 g of 50% ag soln) (100 mL) 50 PDA.HCl (92.0 gof 59% aq soln), IPA 75° C. 18 90 1-bromodecane (62.9 g), 1,6- (100 mL)dibromohexane (9.37 mL), NaOH H₂O (90.0 g of 50% aq soln) (100 mL) 51PDA.HCl (95.3 g of 57% aq soln), IPA 75° C. 18 52 1-bromodecane (62.9g), (100 mL) epichlorohydrin (4.77 mL), HaOH H₂O (90 g of 50% aq soln)(100 mL) 52 PDA.HCl (92.0 g of 57% aq soln), IPA 75° C. 18 871-bromodecane (62.9 g), (100 mL) epichlorohydrin (4.77 mL), NaOH H₂O (90g of 50% aq soln) (100 mL) 53 PDA.HCl (92.0 g of 57% aq soln), IPA 75°C. 18 60 1-bromodecane (62.9 g), (100 mL) epichlorohydrin (6.35 mL),NaOH H₂O (90.0 g of 50% aq soln) (100 mL) 54 PDA.HCl (95.6 g of 56.8% aqsoln), IPA 75° C. 18 71 1-bromodecane (62.9 g), (100 mL)1,6-dibromohexane (3.12 mL), H₂O NaOH (90.0 g of 50% aq soln) (100 mL)55 PDA.HCl (95.6 g of 56.8% aq soln), IPA 75° C. 18 73 1-bromodecane(62.9 g), (100 mL) epichlorohydrin (1.59 mL), NaOH H₂O (90 g of 50% aqsoln) (100 mL) 56 PDA.HCl (54.3 g of 59% aq soln), H₂O 95° C. 18 581-chlorodecane (50.2 g), (200 mL) epichlorohydrin (1.59 mL), NaOH (90 gof 50% aq soln) 57 PDA.HCl (100.0 g of 60% aq soln), H₂O 75° C. 18 861-bromodecane (62.9 g), (300 mL) epichlorohydrin (4.77 mL) NaOH IPA(32.5 g of 50% aq soln) (300 mL) 58 PDMA.HCl (100.0 g of 60% aq IPA 75°C. 18 85 soln), 1-bromodecane (62.9 g), (600 mL) epichlorohydrin (4.77mL), NaOH (32.5 g of 50% aq soln) 59 PDMA.HCl (100.0 g of 60% aq H₂O 75°C. 18 86 soln), 1-bromodecane (62.9 g), (600 mL) epichlorohydrin (0.318mL), NaOH (32.5 g of 50% aq soln) 60 PDMA.HCl (100.0 g of 60% aq H₂O 75°C. 18 74 soln), 1-bromodecane (31.5 g), (600 mL) epichlorohydrin (4.77mL), NaOH (32.5 g of 50% aq soln) 61 PDMA.HCl (100.0 g of 60% aq H₂O 75°C. 18 11 soln), 1,4-butanediol diglycidyl ether (300 mL) (11.74 mL),dodecyl/tetradecyl IPA glycidyl ether (86.4 mL), NaOH (300 mL) (32.5 gof 50% aq soln) 62 PDMA.HCl (100.0 g of 60% aq H₂O 75° C. 18 82 soln),1-bromododecane (62.9 g), (300 mL) epichlorohydrin (9.54 mL), NaOH IPA(32.5 g of 50% aq soln) (300 mL) 63 PDMA.HCl (100.0 g of 60% aq H₂O 75°C. 18 94 soln), 1-bromododecane (125.8 g), (300 mL) epichlorohydrin(4.77 mL), NaOH IPA (32.5 g of 50% aq soln) (300 mL) 64 PDMA.HCl (100.0g of 60% aq H₂O 75° C. 18 81 soln), 1-bromodecane (62.9 g), (300 mL)epichlorohydrin (9.54 mL), NaOH IPA (32.5 g of 50% aq soln) (300 mL) 65PDMA.HCl (100.0 g of 60% aq H₂O 75° C. 18 91 soln), 1-bromodecane (118.0mL), (300 mL) epichlorohydrin (4.77 mL), NaOH IPA (32.5 g of 50% aqsoln) (300 mL) 66 PDMA.HCl (100.0 g of 50% aq H₂O 75° C. 18 66 soln),1-bromododecane (35.8 g), (300 mL) epichlorohydrin (9.54 mL), NaOH IPA(32.5 g of 50% aq soln) (300 mL) 67 PDMA.HCl (100.0 g of 60% aq H₂O 75°C. 18 90 soln), 1-bromododecane (80.7 g), (300 mL) epichlorohydrin (1.59mL), NaOH IPA (32.5 g of 50% aq soln) (300 mL) 68 PDMA.HCl (100.0 g of60% aq H₂O 60° C. 18 39 soln), 1-bromodecane (62.9 g), (600 mL)epichlorohydrin (4.77 mL), NaOH hexanes (32.5 g of 50% aq soln) (1200mL) 69 PDMA.HCl (100.0 g of 60% aq toluene 75° C. 18 60 soln),1-bromodecane (62.9 g), (600 mL) epichlorohydrin (4.77 mL), NaOH (32.5 gof 50% aq soln) 70 PDMA.HCl (100.0 g of 60% aq MeOH 60° C. 18 49 soln),1-bromodecane (62.9 g), (600 mL) epichlorohydrin (4.77 mL), NaOH hexanes(32.5 g of 50% aq soln) (1200 mL) 71 PDMA.HCl (100.0 g of 60% aq H₂O 95°C. 18 82 soln), 1-chlorodecane (50.3 g), (600 mL) epichlorohydrin (4.77mL), NaOH (32.5 g of 50% aq soln) 72 PDMA.HCl (100.0 g of 60% aq H₂O 95°C. 18 75 soln), 1-chlorodecane (65.3 g), (600 mL) epichlorohydrin (1.43mL), NaOH (32.5 g of 50% aq soln) 73 PDMA.HCl (100.0 g of 60% aq H₂O 95°C. 18 66 soln), 1-chlorodecane (32.7 g), (600 mL) epichlorohydrin (1.43mL), NaOH (32.5 g of 50% aq soln) 74 PDMA.HCl (100.0 g of 60% aq H₂O 95°C. 18 59 soln), 1-chlorodecane (16.4 g), (600 mL) epichlorohydrin (1.43mL), NaOH (32.5 g of 50% aq soln)

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the spirit and scope of theinvention as defined by the appended claims.

1. A method for removing bile acids from a mammal comprising the step ofadministering to the mammal a therapeutically effective amount of acrosslinked poly(diallylamine) polymer wherein more than 10% of theamino nitrogen atoms are substituted by an unsubstituted normal orbranched C₂–C₂₄-alkyl group.
 2. The method of claim 1 wherein thepolymer is a homopolymer.
 3. The method of claim 1 wherein the polymeris a copolymer.
 4. The method of claim 1 wherein the polymer comprises arepeat unit of the general formula

wherein R² is hydrogen, a substituted or unsubstituted C₁–C₂₄-alkylgroup, a substituted or unsubstituted arylalkyl group or a substitutedor unsubstituted aryl group; R¹ is a unsubstituted C₃–C₂₄-alkyl group;and X⁻ is a pharmaceutically acceptable anion.
 5. The method of claim 4wherein X⁻ is a conjugate base of an acid selected from the groupconsisting of hydrochloric acid, hydrobromic acid, citric acid, tartaricacid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid,formic acid, maleic acid, fumaric acid, malic acid, succinic acid,malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvicacid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbicacid and acetylglycine.
 6. The method of claim 4 wherein R¹ is an alkylgroup selected from the group consisting of hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, tridecyl and tetradecyl.
 7. The method of claim6 wherein R² is methyl and R¹ is selected from the group consisting ofoctyl, decyl and dodecyl.
 8. The method of claim 1 wherein the polymeris characterized by a repeat unit of the general formula

wherein R is C₃–C₂₄ unsubstituted alkyl group.
 9. The method of claim 8wherein the alkyl group is selected from the group consisting of hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl and tetradecyl.10. The method of claim 1 wherein the polymer comprises a first monomerof the general formula

wherein R¹ is hydrogen, a substituted or unsubstituted C₁–C₂₄-alkylgroup or a substituted or unsubstituted aryl group; R² is anunsubstituted C₃–C₂₄-alkyl group and X⁻is a pharmaceutically acceptableanion; and a second monomer of the general formula

wherein R is hydrogen, a substituted or unsubstituted alkyl group or asubstituted or unsubstituted aryl group.
 11. The method of claim 1wherein the polymer is crosslinked by a multifunctional co-monomer. 12.The method of claim 11 wherein the multifunctional co-monomer isselected from the group consisting of diacrylates, triacrylates,tetraacrylates, dimethacrylates, diacrylamides, dimethacrylamides,diallylacrylamides and polyvinylarenes.
 13. The method of claim 12wherein the multifunctional comonomer is selected from the groupconsisting of ethylene glycol diacrylate, propylene glycol diacrylate,butylene glycol diacrylate, ethylene glycol dimethacrylate, butyleneglycol dimethacrylate, methylene bis(methacrylamide), ethylenebis(acrylamide), ethylene bis(methacrylamide), ethylidenebis(acrylamide), ethylidene bis(methacrylamide), bisphenol Adimethacrylate, bisphenol A diacrylate, pentaerythritol tetraacrylate,trimethylolpropane triacrylate and divinylbenzene.
 14. The method ofclaim 11 wherein the multifunctional comonomer is a multifunctionaldiallylamine.
 15. The method of claim 14 wherein the multifunctionaldiallylamine is a bis(diallylamino)alkane or abis(diallylalkylammonio)alkane.
 16. The method of claim 15 wherein themultifunctional diallylamine is 1,10-bis(diallylmethylammonio)decanedibromide.
 17. The method of claim 1 wherein the polymer is crosslinkedby a bridging unit selected from the group consisting of straight chainor branched, substituted or unsubstituted alkylene groups,diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl)groups.
 18. The method of claim 17 wherein the bridging units areselected from the group consisting of —(CH₂)_(n)—, wherein n is aninteger from about 2 to about 20; —CH₂—CH(OH)—CH₂—; —C(O)CH₂CH₂C(O)—;—CH₂—CH(OH)—O—(CH₂)_(m) —O—CH(OH)—CH₂—, wherein m is 2 to about 4; —C(O)—(C₆H₂(COOH)₂)—C(O)—; and —C(O)NH(CH₂)_(p)NHC(O)—, wherein p is aninteger from about 2 to about 20.